US4730066A - Complex for enhancing magnetic resonance imaging - Google Patents
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- US4730066A US4730066A US06/860,064 US86006486A US4730066A US 4730066 A US4730066 A US 4730066A US 86006486 A US86006486 A US 86006486A US 4730066 A US4730066 A US 4730066A
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- 238000002595 magnetic resonance imaging Methods 0.000 title description 8
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- MMIPFLVOWGHZQD-UHFFFAOYSA-N manganese(3+) Chemical compound [Mn+3] MMIPFLVOWGHZQD-UHFFFAOYSA-N 0.000 claims abstract description 7
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- BFGKITSFLPAWGI-UHFFFAOYSA-N chromium(3+) Chemical compound [Cr+3] BFGKITSFLPAWGI-UHFFFAOYSA-N 0.000 claims abstract description 5
- RJOJUSXNYCILHH-UHFFFAOYSA-N gadolinium(3+) Chemical compound [Gd+3] RJOJUSXNYCILHH-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910021645 metal ion Inorganic materials 0.000 claims description 10
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 abstract description 9
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- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 abstract description 6
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 abstract 1
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- 239000012530 fluid Substances 0.000 description 2
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
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- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910021260 NaFe Inorganic materials 0.000 description 1
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
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- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
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- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/24—Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry
Definitions
- This invention relates to magnetic resonance imaging (MRI), also referred to as nuclear magnetic resonance (NMR) imaging, and more particularly, to methods and composition for enhancing magnetic resonance images of body organs and tissues.
- MRI magnetic resonance imaging
- NMR nuclear magnetic resonance
- the recently developed techniques of MRI or NMR imaging encompass the detection of certain atomic nuclei utilizing magnetic fields and radio-frequency radiation. It is similar in some respects to x-ray computed tomography (CT) in providing a cross-sectional display of the body organ anatomy with excellent resolution of soft tissue detail.
- CT computed tomography
- the images produced constitute a map of the distribution density of protons and/or their relaxation times in organs and tissues.
- the MRI technique is advantageously non-invasive as it avoids the use of ionizing radiation.
- the nuclei under study in a sample e.g. protons
- RF radio-frequency
- these nuclei as they relax subsequently emit RF radiation at a sharp resonant frquency.
- the emitted frequency (RF) of the nuclei depends on the applied magnetic field.
- nuclei with appropriate spin when placed in an applied magnetic field [B, expressed generally in units of gauss or tesla (10 4 gauss)] align in the direction of the field.
- an RF pulse of radiation will excite the nuclei and can be considered to tip the nuclei out of the field direction, the extent of this rotation being determined by the pulse duration and energy.
- the nuclei "relax" or return to equilibrium with the magnetic field,. emitting radiation at the resonant frequency.
- the decay of the signal is characterized by two relaxation times, i.e., T 1 , the spin-lattice relaxation time or longitudinal relaxation time, that is, time taken by the nuclei to return to equilibrium along the direction of the externally applied magnetic field, and T 2 , the spin-spin relaxation time associated with the dephasing of the initially coherent precession of individual proton spins.
- T 1 the spin-lattice relaxation time or longitudinal relaxation time, that is, time taken by the nuclei to return to equilibrium along the direction of the externally applied magnetic field
- T 2 the spin-spin relaxation time associated with the dephasing of the initially coherent precession of individual proton spins.
- MRI may be capable of differentiating tissue types and in detecting diseases which induce physio-chemical changes that may not be detected by x-ray or CT which are only sensitive to differences in the electron density of tissue.
- the images obtainable by MRI techniques also enable the physician to detect structures smaller than those detectable by CT and thereby provide comparable or better spatial resolution.
- the invention is also directed to methods for enhancing magnetic resonance images of body organs and tissues by administering such complexes to a mammal in sufficient amounts to provide enhancement of magnetic resonance images of the body organs and tissues.
- Complexes of the ligands or compounds of the above class with one or more central metal ions such as iron(II), iron(II), manganese(II), manganese(III), gadolinium(III) and chromium(III) are useful for enhancing magnetic resonance images. While such metal ions are themselves paramagnetic in nature and capable of altering the magnetic resonance signal characteristics of body tissues, organs or fluids, they may undesirably exhibit significant toxicity when administered in the form of ionic salts. However, it has been found that the novel complexes of the present invention are relatively or substantially nontoxic and are therefore useful for enhancing magnetic resonance images by favorably altering relaxation times T 1 and T 2 and thereby affording improved contrast between normal and diseased tissues or organs.
- central metal ions such as iron(II), iron(II), manganese(II), manganese(III), gadolinium(III) and chromium(III) are useful for enhancing magnetic resonance images. While such metal ions are themselves paramagne
- the preferred complexes of the invention are those formed from the above ligands or compounds and iron(II), iron(III), manganese(II), manganese(III) and gadolininium(III) as the central metal ion or ions.
- the negatively charged complexes formed by the ligands and central metal ions enumerated above may be further complexed with one or more cations of an inorganic or organic base which are physiologically tolerated such as sodium, potassium, calcium, N-methylglucamine or diethanolamine.
- Illustrative complexes of such ligand and one or more central metal ions from the group consisting of iron(II), iron(III), manganese(II), manganese(III), gadolinium(III) and chromium(III) include monosodium [ethylenediamine-di-(o-hydroxyphenylaceto)]iron(III) hydrate, monosodium [ethylenediamine-di(o-hydroxyphenylaceto)]manganese(III), and monosodium[ethylenediamine-di(o-hydroxyphenylaceto)]gadolinium(III).
- the complexes are formed by reacting the ligand with a metal salt or oxide, the metal being complexed as central metal ions with the carboxylic acid groups of the ligand
- a representative metal complex of the invention namely, monosodium [ethylenediamine-di(o-hydroxyphenylaceto)]iron(III) hydrate, possesses a favorable intravenous toxicity profile and has an LD 50 value of greater than 5.18 mmol/kg. as compared with an LD 50 of approximately 7.2 mmol/kg. for the paramagnetic chelate disodium (diethylenetriaminepentaaceto)gadolinium(III), (GdNa 2 DTPTA), a relatively safe agent for use in magnetic resonance imaging.
- This metal complex of the invention also favorably influences relaxation times.
- the substantially nontoxic metal complexes of the present invention are administered to a mammal in a sufficient amount to provide enhancement of magnetic resonance images of body organs and tissues prior to obtaining a magnetic resonance scan and scans of such organs and tissues with "slices" being taken at the level of the desired organ at various time periods post-administration.
- the complexes of the invention may be used, for example, for enhancing magnetic resonance images of the hepatobiliary system.
- mice Male and female CFl, SQC strain, albino mice (males 16.6-24.9 g in weight; females 18.1-22.8 g in weight) were used. The mice were housed according to standard operating procedures and individually marked with picric acid for identification.
- mice (1 to 6 per dose level) with sexes equally represented received single intravenous injections of the complex of Example 1 via a lateral tail vein at 1.0 ml/min and were observed immediately after dosing and during the 7-day observation period for pharmatoxic reactions.
- An estimated LD 50 value was calculated with an IBM XT computer using a modified Behrens-Reed-Muench Method (Drug Chem. Toxicol. 4:297-305, 1981).
- Example 1 The complex of Example 1, injected as a 5% w/v solution, was found to have an estimated (calculated) LD 50 value of greater than 5.18 mmol/kg. No immediate (0.1-1.0 hr) toxic reactions were noted following injections of the complex of Example 1. However, mild hypoactivity was observed by 4 hours post-administration. All animals appeared normal by the following day and throughout the 7-day observation period. The complex caused a magenta discoloration of the tail, feet, eyes, nose and internal pinna of the ear almost immediately following injection. The intensity of the color appeared to be dose-related. Within 5 minutes post-injection, magenta-colored urine spots appeared on the floor shavings of the holding containers; again color intensity appeared dose-related.
- Example 1 Transient discoloration of highly vascularized external appendages and mild hypoactivity were observed during the first 24 hours post-injection. The discoloration was transient with no apparent signs by 24 hours post-injection. All animals exhibited weight gains during the observation period. Gross examination of internal organs at necropsy was unremarkable. At the maximum dose injected, the complex of Example 1 appears relatively safe.
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- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Complexes of iron(II), iron(III), manganese(II), manganese(III), gadolinium(III) or chromium(III) and a compound of the formula: ##STR1## wherein m=2, 3, 4, or 5, are useful for enhancing magnetic resonance images of body organs and tissues, such as magnetic resonance images of the hepatobiliary system. An illustrative complex of this type is monosodium [ethylenediamine-di(o-hydroxyphenylaceto)]iron(III) hydrate.
Description
This invention relates to magnetic resonance imaging (MRI), also referred to as nuclear magnetic resonance (NMR) imaging, and more particularly, to methods and composition for enhancing magnetic resonance images of body organs and tissues.
The recently developed techniques of MRI or NMR imaging encompass the detection of certain atomic nuclei utilizing magnetic fields and radio-frequency radiation. It is similar in some respects to x-ray computed tomography (CT) in providing a cross-sectional display of the body organ anatomy with excellent resolution of soft tissue detail. In current use, the images produced constitute a map of the distribution density of protons and/or their relaxation times in organs and tissues. The MRI technique is advantageously non-invasive as it avoids the use of ionizing radiation.
While the phenomenon of NMR was discovered in 1945, it is only relative recently that it has found application as a means of mapping the internal structure of the body as a result of the original suggestion of Lauterbur (Nature, 242, 190-191, 1973). The lack of any known hazard associated with the level of the magnetic and radio-frequency fields that are employed renders it possible to make repeated scans on vulnerable individuals. Additionally, any scan plane can readily be selected including transverse, coronal, and sagittal sections.
In an NMR experiment, the nuclei under study in a sample (e.g. protons) are irradiated with the appropriate radio-frequency (RF) energy in a highly uniform magnetic field. These nuclei as they relax subsequently emit RF radiation at a sharp resonant frquency. The emitted frequency (RF) of the nuclei depends on the applied magnetic field.
According to known principles, nuclei with appropriate spin when placed in an applied magnetic field [B, expressed generally in units of gauss or tesla (104 gauss)] align in the direction of the field. In the case of protons, these nuclei precess at a fequency f=42.6 MHz at a field strength of 1 Telsa. At this frequency, an RF pulse of radiation will excite the nuclei and can be considered to tip the nuclei out of the field direction, the extent of this rotation being determined by the pulse duration and energy. After the RF pulse, the nuclei "relax" or return to equilibrium with the magnetic field,. emitting radiation at the resonant frequency. The decay of the signal is characterized by two relaxation times, i.e., T1, the spin-lattice relaxation time or longitudinal relaxation time, that is, time taken by the nuclei to return to equilibrium along the direction of the externally applied magnetic field, and T2, the spin-spin relaxation time associated with the dephasing of the initially coherent precession of individual proton spins. These relaxation times have been established for various fluids, organs and tissues in different species of mammals.
In MRI, scanning planes and slice thickness can be selected without loss of resolution. This permits high quality transverse, coronal and sagittal images to be obtained directly. The absence of any moving parts in MRI equipment promotes a high reliability. It is believed that MRI or NMR imaging has a greater potential than CT for the selective examination of tissue characteristics in view of the fact that in CT, x-ray attenuation coefficients alone determine image contrast whereas at least four separate variables (T1, T2, nuclear spin density and flow) may contribute to the NMR signal. For example, it has been shown (Damadian, Science, 171, 1151, 1971) that the values of the T1 and T2 relaxation in tissues are generally longer by about a factor of 2 in excised specimens of neoplastic tissue compared with the host tissue.
By reason of its sensitivity to subtle physio-chemical differences between organs and/or tissues, it is believed that MRI may be capable of differentiating tissue types and in detecting diseases which induce physio-chemical changes that may not be detected by x-ray or CT which are only sensitive to differences in the electron density of tissue. The images obtainable by MRI techniques also enable the physician to detect structures smaller than those detectable by CT and thereby provide comparable or better spatial resolution.
Continuing efforts are being made to develop imaging agents for enhancing the images obtained through the use of MRI techniques.
Among the several objects of the invention may be noted the provision of novel complexes of certain ligands with one or more central metal ions for use in enhancing magnetic resonance images of body organs and tissues; the provision of such metal complexes which exhibit favorable toxicity profiles; and the provision of methods for enhancing magnetic resonance images of body organs and tissues through the administration of such complexes. Other objects and features will be in part apparent and in part pointed out hereinafter.
Briefly, the invention is directed to complexes comprised of one or more central metal ions of the group consisting of iron(II), iron(III), manganese(II), manganese(III), gadolinium(III) and chromium(III) and a compound of the formula: ##STR2## wherein m=2, 3, 4 or 5. The invention is also directed to methods for enhancing magnetic resonance images of body organs and tissues by administering such complexes to a mammal in sufficient amounts to provide enhancement of magnetic resonance images of the body organs and tissues.
In accordance with the present invention, it has now been found that magnetic resonance images of body organs and tissues may be usefully enhanced through the administration to a mammal of substantially nontoxic metal complexes of a compound of the formula: ##STR3## wherein m=2, 3, 4 or 5.
Complexes of the ligands or compounds of the above class with one or more central metal ions such as iron(II), iron(II), manganese(II), manganese(III), gadolinium(III) and chromium(III) are useful for enhancing magnetic resonance images. While such metal ions are themselves paramagnetic in nature and capable of altering the magnetic resonance signal characteristics of body tissues, organs or fluids, they may undesirably exhibit significant toxicity when administered in the form of ionic salts. However, it has been found that the novel complexes of the present invention are relatively or substantially nontoxic and are therefore useful for enhancing magnetic resonance images by favorably altering relaxation times T1 and T2 and thereby affording improved contrast between normal and diseased tissues or organs.
The preferred complexes of the invention are those formed from the above ligands or compounds and iron(II), iron(III), manganese(II), manganese(III) and gadolininium(III) as the central metal ion or ions. The negatively charged complexes formed by the ligands and central metal ions enumerated above may be further complexed with one or more cations of an inorganic or organic base which are physiologically tolerated such as sodium, potassium, calcium, N-methylglucamine or diethanolamine.
The preferred ligand is one in which m=2, i.e. ethylenediamine-di(o-hydroxyphenylacetic acid), although other ligands of the above formula may also be employed. Illustrative complexes of such ligand and one or more central metal ions from the group consisting of iron(II), iron(III), manganese(II), manganese(III), gadolinium(III) and chromium(III) include monosodium [ethylenediamine-di-(o-hydroxyphenylaceto)]iron(III) hydrate, monosodium [ethylenediamine-di(o-hydroxyphenylaceto)]manganese(III), and monosodium[ethylenediamine-di(o-hydroxyphenylaceto)]gadolinium(III). The complexes are formed by reacting the ligand with a metal salt or oxide, the metal being complexed as central metal ions with the carboxylic acid groups of the ligand.
As shown by the toxicity studies set forth hereinafter, a representative metal complex of the invention, namely, monosodium [ethylenediamine-di(o-hydroxyphenylaceto)]iron(III) hydrate, possesses a favorable intravenous toxicity profile and has an LD50 value of greater than 5.18 mmol/kg. as compared with an LD50 of approximately 7.2 mmol/kg. for the paramagnetic chelate disodium (diethylenetriaminepentaaceto)gadolinium(III), (GdNa2 DTPTA), a relatively safe agent for use in magnetic resonance imaging. This metal complex of the invention also favorably influences relaxation times.
The substantially nontoxic metal complexes of the present invention are administered to a mammal in a sufficient amount to provide enhancement of magnetic resonance images of body organs and tissues prior to obtaining a magnetic resonance scan and scans of such organs and tissues with "slices" being taken at the level of the desired organ at various time periods post-administration. The complexes of the invention may be used, for example, for enhancing magnetic resonance images of the hepatobiliary system.
The following examples illustrate the practice of the invention.
Methanol (36 ml) and ethylenediamine-di(o-hydroxyphenylacetic acid) (3.6 g) were added into a flask under a nitrogen blanket. The solution was stirred and aqueous FeCl3.6H2 O (2.7 g) solution (H2 O, 36 ml) was added dropwise over a period of 30 minutes. The solution was then refluxed for 30 minutes and filtered when hot to remove unreacted ligand. The filtrate was cooled to 25° C. and NaOH solid (1.6 g) was added. The mixture was stirred until all NaOH dissolved. The solution was cooled to 0° C. and added dropwise into acetone (750 ml) with vigorous stirring to precipitate the product. After stirring for 1 hr, the product monosodium [ethylenediamine-di(o-hydroxyphenylaceto)]iron(III) hydrate was collected and dried at 70° L C. Yield 2.4 g (47%). The product was a reddish brown crystal. Tlc analysis: two spots using the upper layer of nBuOH-H2 O-AcOH(4/1/5) system on a silica gel plate. Rf: 0.38 and 0.47.
Elemental analysis: Calculated for C18 H16 N2 O6 NaFe.4H2 O: C, 42.62; H, 4.77; N, 5.52; Na, 4.53; Fe, 11.01. Found: C, 42.16; H, 4.83; N, 5.38; Na, 4.38; Fe, 11.74.
The relaxation times from a 9.99×10-4 M solution in 25% D2 O/H2 O in a 90 MHz NMR experiment were determined to be: T1 =741 msec; 1/T1.sbsb.1 =0.00135 msec-1 ; T2 =85 msec; 1/T2 =0.0118 msec-1.
An acute intravenous toxicity study was carried out with the complex of Example 1.
Dilutions of the complex were prepared as necessary using Sterile Water for Injection, U.S.P. (Abbott Laboratories, North Chicago, Ill.).
Male and female CFl, SQC strain, albino mice (males 16.6-24.9 g in weight; females 18.1-22.8 g in weight) were used. The mice were housed according to standard operating procedures and individually marked with picric acid for identification.
The mice (1 to 6 per dose level) with sexes equally represented received single intravenous injections of the complex of Example 1 via a lateral tail vein at 1.0 ml/min and were observed immediately after dosing and during the 7-day observation period for pharmatoxic reactions.
An estimated LD50 value was calculated with an IBM XT computer using a modified Behrens-Reed-Muench Method (Drug Chem. Toxicol. 4:297-305, 1981).
The complex of Example 1, injected as a 5% w/v solution, was found to have an estimated (calculated) LD50 value of greater than 5.18 mmol/kg. No immediate (0.1-1.0 hr) toxic reactions were noted following injections of the complex of Example 1. However, mild hypoactivity was observed by 4 hours post-administration. All animals appeared normal by the following day and throughout the 7-day observation period. The complex caused a magenta discoloration of the tail, feet, eyes, nose and internal pinna of the ear almost immediately following injection. The intensity of the color appeared to be dose-related. Within 5 minutes post-injection, magenta-colored urine spots appeared on the floor shavings of the holding containers; again color intensity appeared dose-related. Transient discoloration of highly vascularized external appendages and mild hypoactivity were observed during the first 24 hours post-injection. The discoloration was transient with no apparent signs by 24 hours post-injection. All animals exhibited weight gains during the observation period. Gross examination of internal organs at necropsy was unremarkable. At the maximum dose injected, the complex of Example 1 appears relatively safe.
In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.
As various changes could be made in the above constructions without departing from the scope of the invention, it is intended that all matter contained in the above description or shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.
Claims (1)
1. A complex for use in enhancing magnetic resonance images of body organs and tissues, said complex comprising a central metal ion selected from the group consisting of manganese(II), manganese(III), gadolinium(III) and chromium(III) and a compound of the formula: ##STR4## wherein m=2, 3, 4 or 5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/860,064 US4730066A (en) | 1986-05-06 | 1986-05-06 | Complex for enhancing magnetic resonance imaging |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/860,064 US4730066A (en) | 1986-05-06 | 1986-05-06 | Complex for enhancing magnetic resonance imaging |
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| Publication Number | Publication Date |
|---|---|
| US4730066A true US4730066A (en) | 1988-03-08 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US06/860,064 Expired - Fee Related US4730066A (en) | 1986-05-06 | 1986-05-06 | Complex for enhancing magnetic resonance imaging |
Country Status (1)
| Country | Link |
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| US (1) | US4730066A (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5025101A (en) * | 1990-06-21 | 1991-06-18 | Exxon Research & Engineering Company | Novel tetranuclear manganese complexes |
| US5039512A (en) * | 1986-08-04 | 1991-08-13 | Salutar, Inc. | NMR imaging with paramagnetic polyvalent metal salts of poly-(acid-alkylene-amino)-alkanes |
| WO1993006148A1 (en) * | 1991-09-24 | 1993-04-01 | Unger Evan C | Copolymers and their use as contrast agents in magnetic resonance imaging and in other applications |
| US5219553A (en) * | 1986-08-04 | 1993-06-15 | Salutar, Inc. | Composition of a n-carboxymethylated tetraazacyclododecane chelating agent, a paramagnetic metal and excess calcium ions for MRI |
| US5312617A (en) * | 1991-05-23 | 1994-05-17 | Unger Evan C | Liposoluble compounds useful as magnetic resonance imaging agents |
| US5314681A (en) * | 1988-12-23 | 1994-05-24 | Nycomed Innovation Ab | Composition of positive and negative contrast agents for electron spin resonance enhanced magnetic resonance imaging |
| US5399340A (en) * | 1987-09-24 | 1995-03-21 | Schering Aktiengesellschaft | Use of amide complex compounds |
| US5628983A (en) * | 1990-04-02 | 1997-05-13 | Nycomed Imaging | Squid magnetometry using paramagnetic metal chelates |
| WO2002000604A1 (en) * | 2000-06-28 | 2002-01-03 | Universidad Complutense De Madrid | Novel method for preparing bis(2-hydroxyaryl)aminoacetic acids using cyanide transfer agents |
| CN106831885A (en) * | 2017-01-20 | 2017-06-13 | 四川隆桥化工集团有限公司 | The preparation method of ethylenediamine o-hydroxy phenylacetic acid ferrisodium |
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| US4472509A (en) * | 1982-06-07 | 1984-09-18 | Gansow Otto A | Metal chelate conjugated monoclonal antibodies |
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| US4472509A (en) * | 1982-06-07 | 1984-09-18 | Gansow Otto A | Metal chelate conjugated monoclonal antibodies |
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Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5039512A (en) * | 1986-08-04 | 1991-08-13 | Salutar, Inc. | NMR imaging with paramagnetic polyvalent metal salts of poly-(acid-alkylene-amino)-alkanes |
| US5219553A (en) * | 1986-08-04 | 1993-06-15 | Salutar, Inc. | Composition of a n-carboxymethylated tetraazacyclododecane chelating agent, a paramagnetic metal and excess calcium ions for MRI |
| US5399340A (en) * | 1987-09-24 | 1995-03-21 | Schering Aktiengesellschaft | Use of amide complex compounds |
| US5314681A (en) * | 1988-12-23 | 1994-05-24 | Nycomed Innovation Ab | Composition of positive and negative contrast agents for electron spin resonance enhanced magnetic resonance imaging |
| US5628983A (en) * | 1990-04-02 | 1997-05-13 | Nycomed Imaging | Squid magnetometry using paramagnetic metal chelates |
| US5025101A (en) * | 1990-06-21 | 1991-06-18 | Exxon Research & Engineering Company | Novel tetranuclear manganese complexes |
| US5312617A (en) * | 1991-05-23 | 1994-05-17 | Unger Evan C | Liposoluble compounds useful as magnetic resonance imaging agents |
| US5466438A (en) * | 1991-05-23 | 1995-11-14 | Imarx Pharmaceutical Corp. | Liposoluble compounds useful as magnetic resonance imaging agents |
| US5624662A (en) * | 1991-05-23 | 1997-04-29 | Imarx Pharmaceutical Corporation | Liposoluble heterocyclic compounds useful as magnetic resonance imaging agents |
| US5762910A (en) * | 1991-05-23 | 1998-06-09 | Imarx Pharmaceutical Corp. | Liposoluble compounds useful as magnetic resonance imaging agents |
| US6010682A (en) * | 1991-05-23 | 2000-01-04 | Imarx Pharmaceuticals Corp. | Liposoluble compounds useful as magnetic resonance imaging agents |
| US5385719A (en) * | 1991-09-24 | 1995-01-31 | Unger; Evan C. | Copolymers and their use as contrast agents in magnetic resonance imaging and in other applications |
| US5458127A (en) * | 1991-09-24 | 1995-10-17 | Imarx Pharmaceutical Corp. | Copolymers and their use as contrast agents in magnetic resonance imaging and in other applications |
| US5517993A (en) * | 1991-09-24 | 1996-05-21 | Imarx Pharmaceutical Corp. | Copolymers and their use as contrast agents in magnetic resonance imaging and in other applications |
| WO1993006148A1 (en) * | 1991-09-24 | 1993-04-01 | Unger Evan C | Copolymers and their use as contrast agents in magnetic resonance imaging and in other applications |
| WO2002000604A1 (en) * | 2000-06-28 | 2002-01-03 | Universidad Complutense De Madrid | Novel method for preparing bis(2-hydroxyaryl)aminoacetic acids using cyanide transfer agents |
| ES2174712A1 (en) * | 2000-06-28 | 2002-11-01 | Univ Madrid Complutense | Novel method for preparing bis(2-hydroxyaryl)aminoacetic acids using cyanide transfer agents |
| CN106831885A (en) * | 2017-01-20 | 2017-06-13 | 四川隆桥化工集团有限公司 | The preparation method of ethylenediamine o-hydroxy phenylacetic acid ferrisodium |
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